Channelling the Force to Reprogram the Matrix: Mechanosensitive Ion Channels in Cardiac Fibroblasts

Figures

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  Figure 1. The pathophysiological effect of mechanical forces on the heart. (A) The heart is subject to mechanical forces such as stretch and compression as a consequence of the rhythmic beating of the heart, shear stress due to blood flow, and tension due to the stiffening of tissues under certain physiological and pathophysiological conditions. (B) Mechanical forces which occur during pathophysiological conditions prompt cardiac fibrosis and cardiomyocyte hypertrophy, resulting in stiffening and thickening of the muscular walls of the heart. (C) Cardiac fibroblasts are thought to be sensitive to the changes in mechanical forces of the heart. In culture, cardiac fibroblasts are sensitive to the stiffness of the culture surface and tensile forces, such as stretch and compression. In response to tensile forces and surface stiffness, cardiac fibroblasts transdifferentiate into myofibroblasts and proliferate more rapidly.

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  Figure 2. Schematic diagram of TRPC6 structure and signalling in cardiac fibroblasts. (A) Basic structure of alpha subunit of TRPC6. Each TRPC6 alpha subunit is comprised of six transmembrane-spanning domains (S1–S6), with a pore loop between S5 and S6, ankyrin repeats (AnkR) at the amino terminus, and a TRP-box (TRP) and calmodulin- and IP3 receptor-binding (CIRB) domain at the carboxyl termini. (B) Known TRPC6 homotetrameric ion channel signalling in cardiac fibroblasts. Ang II and TGF-β can upregulate cardiac fibroblast TRPC6 gene expression resulting in increased Ca2+ influx. TRPC6-mediated Ca2+ entry is coupled to cardiac myofibroblast differentiation via activation of the calcineurin–NFAT signalling pathway. See main text for details.

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  Figure 3. Schematic diagram of TRPM7 structure and cardiac fibroblast signalling. (A) Basic structure of alpha subunit of TRPM7. Each TRPM7 alpha subunit is comprised of six transmembrane-spanning domains (S1–S6), with a pore loop between S5 and S6, melastatin homology domains (MHD) at the amino termini, and a TRP-box (TRP), a coiled-coil domain (CCD), and an atypical α-type serine/threonine protein kinase domain (α-kinase) at the carboxyl termini. (B) Known TRPM7 homotetrameric ion channel signalling in cardiac fibroblasts. Ang II drives activation of TRPM7 and is coupled to increased nuclear activity of Ki-67 and proliferating cell nuclear antigen (PCNA), as well as upregulation of markers of fibrosis including connective tissue growth factor (CTGF). H2O2 activates TRPM7 and promotes MF differentiation and ECM remodelling via the ERK-1/2 MAP kinase pathway. TGF-β1 and isoproterenol treatment both induce upregulation of TRPM7 expression and Ca2+ influx leading to myofibroblast differentiation. TRPM7 expression can be inhibited by miR-135a expression. See main text for details.

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  Figure 4. Schematic diagram of TRPV1 and TRPV4 structure and cardiac fibroblast signalling. (A) Basic structure of alpha subunit of TRPV1. (B) Basic structure of alpha subunit of TRPV4. (A-B) Each TRPV1 and TRPV4 alpha subunit is comprised of six transmembrane-spanning domains (S1–S6), with a pore loop between S5 and S6, ankyrin repeats (AnkR) at the amino terminus, and a TRP-box at the carboxyl terminus. (C) Known TRPV1 and TRPV4 homotetrameric ion channel signalling in cardiac fibroblasts. Capsaicin activates TRPV1 and inhibits Ang II-induced cell proliferation. TRPV1 activation also inhibits isoproterenol-induced cell proliferation, and attenuates isoproterenol-induced ECM synthesis, cell proliferation and myofibroblast differentiation by blocking downregulation of p-Akt, p-eNOS, NO and cGMP. TGF-β activates TRPV4, inducing Ca2+ influx and promoting RhoA signalling, upregulation of MRTF-A transcription factor, and myofibroblast differentiation. See main text for details.

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  Figure 5. Schematic diagram of Piezo1 structure and cardiac fibroblast signalling. (A) Predicted basic alpha subunit structure of mammalian Piezo1. Piezo1 is predicted to have a peripheral transmembrane segment comprised of nine transmembrane helical units (THU1-THU9), an anchor domain (α1-3), C-terminal extracellular domain (CED), C-terminal domain (CTD), and a beam-like structure facing the intracellular surface. (B) Known Piezo1 homotrimeric ion channel signalling in cardiac fibroblasts. Mechanical stretch and Yoda1 both activate Piezo1 in cardiac fibroblasts. Mechanical stimulation of Piezo1 activates the potassium-selective Ca2+-activated channel of large conductance (BKCa). Yoda1 activation of Piezo1 activates the p38α MAPK pathway and stimulates IL-6 gene expression and protein secretion. See main text for details.

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  Figure 6. Schematic diagram of TREK-1 and KATP structure and cardiac fibroblast signalling. (A) Predicted basic alpha subunit structure of TREK-1. TREK-1 subunits are composed of four transmembrane domains (M1-M4) and two pore forming P-loops (P1-P2). (B) Predicted basic alpha subunit structure of KATP. Each KATP alpha subunit consists of one ABC transporter subunit (SUR) and one inward rectifier K+ channel (Kir) subunit (C) Known TREK-1 homodimeric ion channel and KATP tetrameric ion channel signalling in cardiac fibroblasts. Cardiac fibroblast TREK-1 activation promotes cardiac fibrosis. Membrane stretch, TGF-β and EGF modulate JNK and c-Jun phosphorylation via a TREK-1-dependent mechanism. KATP gene expression is upregulated during cardiac fibroblast to myofibroblast transdifferentiation. Once active, KATP attenuates Ang II-induced proliferation and endothelin-1 expression, while also inhibiting myofibroblast differentiation. See main text for details.